Abstract: A critical aspect of designing biomaterial carriers for cells and drug delivery is tuning and controlling the material[unreadable]s degradation behavior. In the last decade, there has been considerable interest in using photochemistry to produce biomaterials because of the ability to form scaffolds in situ under physiological conditions, in the presence of tissues, cells, proteins and DNA. Because photochemistry has been established as an effective method to form biomaterials under physiological conditions, integrating photochemistry as a degradation mechanism should be equally biocompatible, affording spatial and temporal control over the chemical, mechanical and physical properties of the biomaterial, and allowing for the controlled and triggerable release of therapeutic agents. Photodegradable biomaterials enable strict temporal control of the degradation process, by controlling the exposure to and dosage of light, coupled with precise spatial resolution by using photomasks and/or focused laser beams. The PI has synthesized a series of photodegradable linkers based on a photolabile nitrobenzylether moiety, whose degradation rate is a function of wavelength, molar absorptivity, and light intensity. The PI proposes to use combinations of these photodegradable linkers to create complex 3D cell-instructive microenvironments through multi-stage release of chemical cues (i.e. small molecules, protein growth factors, DNA, siRNA, cell-adhesive peptides) and physical patterning to direct cell growth. No other biomaterial platform has the potential to recapture the complex cascade of signals seen during tissue development. Such a set of tools to externally control and manipulate the chemical and physical microenvironment of cells represents a transformative approach to biomaterials and tissue engineering, with far-reaching implications in other disciplines. Public Health Relevance: Developing a photodegradable platform to recreate the complex chemical and physical microenvironment experienced by cells in vivo has the potential to affect our basic understanding of development and disease, and 3D in vitro models of disease will allow for therapeutic screening. Photodegradable biomaterials can also be used as a tool to deliver therapeutic agents and direct cell growth in vivo. This research has the potential to impact public health through improved understanding of diseases, and improved treatments for disease.